PROJECT SUMMARY/ABSTRACT The visual system exhibits a heightened sensitivity to the quality visual experience during an interval late in development termed the critical period. Discordant vision during the critical period is the cause of amblyopia, a prevalent visual disorder in children. Treatment of amblyopia is most effective in children before the close of the critical period. Subsequently, the flexibility with brain circuitry diminishes in adulthood and effective therapy is more difficult. In a mouse model of amblyopia, disrupting normal vision by closing one eye for only a few days (monocular deprivation, MD) during the critical period, but not thereafter, also perturbs the normal binocularity of neurons in visual cortex and decreases visual acuity. Yet how these adaptive changes, or plasticity, first emerge within neurons that form the circuits in visual cortex is poorly understood. Likewise, how plasticity propagates from the first neurons to adapt to other neurons connected to these neurons by synapses is unclear. The short duration of the critical period in mice is one factor impeding the study of how the greater plasticity confined to the critical period contributes to the induction as well as recovery from amblyopia. The nogo-66 receptor gene (ngr1) is required to close the critical period. In ngr1 mutant mice, plasticity during the critical period is normal, but it is retained in adult mice. Importantly, ngr1 mutant mice spontaneously recover visual acuity in this model of amblyopia. In the proposed research, we take advantage of this extended critical period in ngr1 mice to investigate what is unique about plasticity during the critical period that promotes recovery from amblyopia. We compare how MD alters the function and connectivity of populations of neurons in visual cortex with a combination of sophisticated repeated in vivo calcium imaging and laser-scanning photostimulation synaptic mapping. We will begin to unravel how plasticity within visual cortex proceeds during abnormal vision (MD), as well as how this plasticity is restricted to the critical period with these experiments. In addition to improving understanding of how experience-dependent plasticity changes the function of brain circuits, these studies may reveal new avenues for developing therapeutic approaches to treat amblyopia and perhaps other neurodevelopmental disorders that result from maladaptive developmental plasticity.